This invention relates to processes for electrophilically fluorinating .beta.-dicarbonyls to form the corresponding .alpha.-fluorinated-.beta.-dicarbonyls, with the use of bis-fluoroxydifluoromethane (BDM) in the presence of an acid.
Although bis-fluoroxydifluoromethane (CF.sub.2 (OF).sub.2), and to a much greater extent the monofluoroxy compound, fluoroxytrifluoromethane (CF.sub.3 OF), have been used to carry out a number of electrophilic fluorinations (see, e.g., U.S. Pat. No. 4,766243 and Fifolt et al., "Fluorination of Aromatic Derivatives with Fluoroxytrifluoromethane and Bis(fluoroxy)difluoromethane," J. Org. Chem. 1985, 50(23), 4576), the inventors are not aware of any prior art teaching their use for the fluorination of 1,3-dicarbonyls.
On the other hand, there is evidence in the art suggesting that O--F bond-containing compounds are not particularly effective for fluorinating 1,3-dicarbonyls. For example, the use of acetyl hypofluorite, another O--F bond containing compound, has been used successfully in the fluorination of enolate salts of ketoesters, but has proven to be less effective in the fluorination of neutral ketoesters. See, e.g., Patrick, "Electrophillic Fluorination of Carbon-Hydrogen Bonds," Chemistry of Organic Fluorine Compounds II 1995, 133. Similarly, cesium fluoroxysulfate (CsSO.sub.3 (OF)) gave only a 44% yield of the desired monofluorinated product and 19% of the difluorinated product on reaction with relatively nucleophilic 2,4-pentanedione. See, e.g., Stavber et al., "Room-temperature Reactions of CsSO.sub.4 F with Organic Molecules containing Heteroatoms," J. Chem. Soc., Chem. Comm., 1983, 563.
Previously, 1,3-dicarbonyls, such as .beta.-diketones and .beta.-ketoesters, having the formula: ##STR1##
where R.sub.1 is H, alkyl or alkoxy, R.sub.2 is H, alkyl or perfluoroalkyl, and R.sub.3 is H, Cl, Br, I or alkyl, have been fluorinated directly with fluorine in acidic solvents or in polar solvents containing acidic, or weakly basic, polar additives. While this methodology has been reasonably selective, the desired monofluorination products still contain 10-35% radical fluorination impurities (the term "radical fluorination impurities" refers to products resulting from fluorination at R.sub.1 and/or R.sub.2 in Formula I above) at substrate loadings of only 5-10 wt. % in the chosen solvent. See, e.g., U.S. Pat. No. 5,569,778 (Umemoto et al.)
Another technique for fluorinating the alpha carbon in .beta.-dicarbonyls comprises directly fluorinating .beta.-dicarbonyl compounds with fluorine in a reactive medium comprising a radical scavenger, such as oxygen, that inhibits side reactions between fluorine and acid additives. See the inventors' prior U.S. patent application Ser. No. 09/432,723, filed Nov. 1, 1999.
EP 0891962 (Nukui et al.) discloses a process for preparing fluorinated dicarbonyl compounds comprising reacting dicarbonyl compounds and fluorine gas without any solvent and in the presence of at least one acid selected from the group consisting of trifluoromethanesulfonic acid (i.e., triflic acid), methanesulfonic acid, hydrofluoric acid, sulfuric acid, trifluoroacetic acid, boron trifluoride and sulfonated polymers. Nukui et al. discloses that the substrate loadings have been substantially increased in very strong acids (up to 88 wt. % methyl-3-oxopentanoate (MOP) in highly acidic triflic acid), but gives only 16 wt. % fluorination impurities, including 2,2-difluorinated impurity. However, these fluorinated impurities are often difficult to separate from the desired product and many of them are carried forward in subsequent reaction steps.
Additionally, higher purity fluorinated dicarbonyls have been obtained by a number of multistep methods. For example, the dicarbonyl compound has been converted, using a strong base, into its enolate salt which has been fluorinated by a more selective, but costly, electrophilic fluorinating reagent. By this method, the dicarbonyl compound has been chlorinated and then fluorinated by halogen exchange. This method gives only moderate yields (30-80%) of fluorinated product, which must still be purified by fractional distillation. See, e.g., U.S. Pat. No. 5,391,811 (Bohm et al).
Despite the foregoing developments, there is still room in the art for improved fluorination methods.
All references cited herein are incorporated herein by reference in their entireties.